Mitochondrial pore and synaptic stress in Alzheimer's disease

阿尔茨海默病中的线粒体孔和突触应激

基本信息

批准号：
8264172
负责人：
Heng Du
金额：
$ 9万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-15 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8264172
关键词：
AD transgenic mice Address Age Alzheimer&apos s Disease Animals Attenuated Axon Biological Assay Calcium Defect Dendritic Spines Development Energy Metabolism Environment Foundations Generations Genetic Health Hippocampus (Brain)Learning Maintenance Mediating Membrane Membrane Potentials Memory Mentors Mitochondria Mitochondrial Swelling Morphology Mus Neurons Oxidative Stress Oxygen Consumption Pathogenesis Pathology Permeability Play Principal Investigator Property Proteins Research Resistance Respiration Role Stress Synapses Synaptic Transmission Testing Transgenic Mice Vertebral column base career cell motility cyclophilin D density enzyme activity insight mitochondrial dysfunction mitochondrial membrane mitochondrial permeability transition pore mouse model novel novel therapeutic intervention overexpression programs response synaptic failure synaptic function trafficking

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial dysfunction and synaptic loss are early pathological features of Alzheimer's disease. Recent studies indicate that mitochondrial alterations in AD underlie Abeta-mediated synaptic pathology as evidenced by the observations: 1) significant correlation of mitochondrial dysfunction with synaptic loss in AD; and 2) the protection of mitochondria attenuates Abeta -induced synaptic changes. However, the mechanisms of Abeta -induced mitochondrial dysfunction and the consequent synaptic damages have not fully delineated. Notably, mitochondria in neurons are heterogeneous in their properties. A sub-group of neuronal mitochondria locating at synapses or namely synaptic mitochondria play a pivotal role in maintaining synaptic activity/function due to their physical proximity to synapses. Thus, to elucidate the mechanisms underlying Abeta -potentiated synaptic mitochondrial dysfunction is of great significance to deepen our understanding of the synaptic pathology in the pathogenesis of the AD. In the preliminary studies, we have demonstrated that synaptic mitochondria undergo increased propensity towards cyclophilin D (cypD)-mediated mitochondrial permeability transition pore (mPTP) in the Abeta milieu, transgenic AD mice overexpressing Abeta. Along with these changes, Abeta -insulted synaptic mitochondria underwent respiration defects. In addition, Abeta treatment resulted in decreased axonal mitochondrial density and the loss of synapses in cultured hippocampal neurons. As a contrast, these detrimental effects on synaptic mitochondrial and synaptic alterations were significantly attenuated by the blockade of cypD through genetic depletion of cypD. Thus, I have formulated a hypothesis that cypD-mediated mPTP is a potential mechanism underlying Abeta-induced synaptic mitochondrial dysfunction and synaptic alterations. To address this concept, I will utilize an AD mouse model (APP mice) and a novel genetically manipulated transgenic mouse model (genetic cypD-deficient APP mice) as well as cypD-deficiency hippocampal neuron cultures for the studies proposed in this application. This project contains three aims: 1). to determine the impact of cypD-mediated mPTP on synaptic mitochondrial function in APP mice; 2) to determine the impact of cypD-mediated mPTP on synaptic (axonal) mitochondrial dynamics and motility in Abeta milieus; and 3) to determine whether cypD-mediated synaptic mitochondrial dysfunction contributes to Abeta -induced synaptic alterations in APP mice. Upon the completion of this project, I will determine the involvement of cypD mediated mPTP in Abeta induced synaptic mitochondrial dysfunction, and the impact of cypD mediated mPTP on synaptic mitochondrial dynamics and motility, and synaptic function as well as animal learning/memory ability in APP/ Abeta overexpressing mice. Finding derived from this study will have positive impact on the development of new therapeutic approaches for AD treatment. This project will also serve as a firm foundation of my scientific career to establish a research direction distinct from my mentors' by the combination of synaptic mitochondrial dysfunction and synaptic alterations in AD.

描述（由申请人提供）：线粒体功能障碍和突触损失是阿尔茨海默氏病的早期病理特征。最近的研究表明，AD基础ABETA介导的突触病理基础的线粒体改变，这是由观察结果证明的：1）线粒体功能障碍与AD突触丧失的显着相关性； 2）线粒体的保护减弱了Abeta诱导的突触变化。但是，Abeta诱导的线粒体功能障碍和随之而来的突触损伤的机制尚未完全划定。值得注意的是，神经元中的线粒体的性质是异质的。神经元线粒体的亚组位于突触或突触线粒体，在维持突触/功能上，由于其与突触的物理接近，在维持突触活动/功能方面起着关键作用。因此，为了阐明ABETA启用的突触线粒体功能障碍的机制对于加深我们对AD发病机理中突触病理学的理解具有重要意义。在初步研究中，我们已经证明突触线粒体在Abeta Milieu，转基因AD小鼠Abeta过表达Abeta的Abeta Milieu中经历了对环蛋白D（CYPD）介导的线粒体通透性转变孔（MPTP）的倾向。随着这些变化，ABETA植入的突触线粒体发生了呼吸缺陷。此外，ABETA治疗导致轴突线粒体密度降低和培养的海马神经元突触丧失。相反，这些有害的对突触线粒体和突触改变的有害作用通过CYPD的阻断而通过CYPD的遗传耗竭显着减弱。因此，我提出了一个假设，即CYPD介导的MPTP是基于Abeta诱导的突触线粒体功能障碍和突触改变的潜在机制。为了解决这个概念，我将利用AD小鼠模型（APP小鼠）和一种新型的遗传操纵转基因小鼠模型（遗传CYPD缺陷型APP小鼠）以及CYPD缺乏海马神经元培养此应用。该项目包含三个目标：1）。确定CYPD介导的MPTP对APP小鼠突触线粒体功能的影响； 2）确定CYPD介导的MPTP对Abeta Milieus突触（轴突）线粒体动力学的影响； 3）确定CYPD介导的突触线粒体功能障碍是否有助于ABTA诱导的APP小鼠突触改变。该项目完成后，我将确定CYPD介导的MPTP参与ABETA诱导的突触线粒体功能障碍，以及CYPD介导的MPTP对突触线粒体动力学和运动的影响，以及突触功能以及App/ Abeta Abeta expeccepression expectapress expecters expecters expecters Miles sembistic ins nemberic ins intaptic。从这项研究中得出的发现将对新的AD治疗方法的发展产生积极影响。该项目还将成为我科学职业的坚定基础，以建立与导师的研究方向通过突触线粒体功能障碍和AD突触改变的结合。